Ah. Horwitz et al., CHIMERIC IMMUNOGLOBULIN LIGHT-CHAINS ARE SECRETED AT DIFFERENT LEVELS- INFLUENCE OF FRAMEWORK-1 AMINO-ACIDS, Molecular immunology, 31(9), 1994, pp. 683-692
Immunoglobulin light chain proteins are generally thought to be readil
y secreted without their corresponding heavy chains; non-secreted ligh
t chains have been viewed as aberrant forms. We have re-examined this
assumption by expressing chimeric mouse-human light chains constructed
for 12 mouse antibodies (mouse variable regions fused to a human kapp
a light chain constant region) in Sp2/0 and CHO cells. Five of the 12
light chains were either poorly secreted or not secreted at all. There
was approximately a five-fold difference in the levels of secreted li
ght chain between the highest poor secretor and the lowest good secret
or. All of these light chains formed functional chimeric IgGs, which w
ere secreted at similar levels, when co-expressed with their respectiv
e chimeric mouse-human heavy chains (mouse variable regions fused to a
human gamma-1 heavy chain constant region). The influence of variable
region amino acids on light chain secretion was examined by replacing
the Framework-1 region of three poorly-secreted chimeric light chains
with that of a readily-secreted light chain. For two of the light cha
ins, secretion levels increased approximately 30- and 100-fold relativ
e to that of the unmodified light chains. Comparison of the Framework-
1 amino acid sequence of the poorly- and readily-secreted light chains
revealed an asparagine (N) and proline (P) at positions 11 and 12, re
spectively of these poorly-secreted light chains and a leucine (L) and
serine (S) in the same region for some of the readily secreted light
chains. Alteration of the NP to LS for one of the poorly-secreted ligh
t chains resulted in an approximately seven-fold increase in light cha
in secretion over that of the native form of the poorly-secreted light
chain. We conclude from these studies that poor secretion can be a na
turally occurring state for normal light chains and that amino acids w
ithin Framework-1 contribute to poor secretion for some of the light c
hains.